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TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered the first clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. The xanthine class of modulators includes the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Targeting this pocket may be a promising strategy for TRPC1/4/5 drug discovery. Here we report the first structure of a small molecule-bound TRPC1/4/5 channelhuman TRPC5 in complex with the xanthine Pico145to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn 2+ ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators.

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Understanding animal foraging ecology requires large samples sizes spanning broad environmental and temporal gradients. For pollinators, this has been hampered by the laborious nature of morphologically identifying pollen. Metagenetic pollen analysis is a solution to this issue, but the field has struggled with poor quantitative performance. Building upon prior laboratory and bioinformatic methods, we applied quantitative multi-locus metabarcoding to characterize the foraging ecology of honey bee colonies situated along an urban-agricultural gradient in central Ohio, USA. In cross-validating a subset of our metabarcoding results using microscopic palynology, we find strong concordance between the molecular and microscopic methods. Our results show that, relative to the agricultural environment, urban and suburban environments were associated with higher taxonomic diversity and temporal turnover of honey bee pollen forage. This is likely reflective of the fine-grain heterogeneity and high beta diversity of urban floral landscapes at the scale of honey bee foraging. Our work also demonstrates the power of honey bees as environmental samplers of floral community composition at large spatial scales, aiding in the distinction of taxa characteristically associated with urban or agricultural land use from those distributed ubiquitously across our landscape gradient.

Background: Limited data suggests that morbid obesity (Body Mass Index-BMI > 35 kg/m 2 ) increases complications after left ventricular assist device (LVAD) implantation and after heart transplantation (HTx). We comprehensively compared LVAD and heart transplantation (HTx) outcomes in patients with and without morbid obesity.Methods: Society of Thoracic Surgeons (STS) and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) data on LVAD and HTx surgeries at our institution from 2008-2014 was analyzed. Patients were divided into two groups, BMI ≥ 35 and BMI < 35.Results: Of the 157 LVADs implanted, 121 (77%) were in patients with a BMI < 35 and 36 (23%) were in patients with a BMI ≥ 35. Morbidly obese patients were younger (47 ± 12.7 yrs vs. 55 ± 13.4 yrs), had more females (44% vs. 24%), had higher right heart catheterization pressures, and fewer prior myocardial infarctions (22% vs. 46%), all p < 0.05. Preoperative morbidities, INTERMACS class, and LVAD implantation designation were comparable between both groups. The BMI ≥ 35 group had more postoperative and device complications, but only bleeding requiring reoperation (42% vs. 22% p = 0.03) and mean number of driveline infections were statistically significant (2.4 ± 1.7 vs. 1.2 ± 0.5 p = 0.02). At a mean follow-up of 27.3 ± 20.5 months, fewer morbidly obese patients received a HTx (19% vs. 33% p = 0.15) after relatively longer wait times (619 ± 372 vs. 403 ± 342 days, p = 0.1). After HTx, morbidly obese patients had more reoperations (57% vs. 15% p = 0.03). Conclusions:Morbidly obese patients requiring LVAD support encounter higher postoperative complications and wait longer for heart transplantation, however in selected group of patients HTx and graft survival is comparable.